Direct thrombin inhibitor: Difference between revisions
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==Overview== | ==Overview== | ||
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==Types== | ==Types== | ||
There are two types of DTIs, dependent on their interaction with the thrombin molecule. ''Bivalent'' DTIs ([[hirudin]] and analogs) bind both to the active site and exosite 1, while univalent DTIs bind only to the active site.<ref name=DiNisio>{{cite journal | author = Di Nisio M, Middeldorp S, Büller H | title = Direct thrombin inhibitors. | journal = N Engl J Med | volume = 353 | issue = 10 | pages = 1028-40 | year = 2005 | id = PMID 16148288}}</ref> | There are two types of DTIs, dependent on their interaction with the thrombin molecule. ''Bivalent'' DTIs ([[hirudin]] and analogs) bind both to the active site and exosite 1, while univalent DTIs bind only to the active site.<ref name="DiNisio">{{cite journal | author = Di Nisio M, Middeldorp S, Büller H | title = Direct thrombin inhibitors. | journal = N Engl J Med | volume = 353 | issue = 10 | pages = 1028-40 | year = 2005 | id = PMID 16148288}}</ref> | ||
===Bivalent=== | ===Bivalent=== | ||
[[Hirudin]] and derivatives were originally discovered in ''[[Hirudo medicinalis]]'': | [[Hirudin]] and derivatives were originally discovered in ''[[Hirudo medicinalis]]'': | ||
* [[Bivalirudin]] (transient inhibition - is cleaved by thrombin) | |||
* [[Desirudin]] | |||
* [[Hirudin]] | * [[Hirudin]] | ||
* [[Lepirudin]] | * [[Lepirudin]] | ||
===Univalent=== | ===Univalent=== | ||
Univalent DTIs include: | Univalent DTIs include: | ||
* [[Argatroban]] | * [[Argatroban]] | ||
* [[Dabigatran]] | |||
* [[Melagatran]] (and its prodrug ximelagatran) | * [[Melagatran]] (and its prodrug ximelagatran) | ||
==Uses== | ==Uses== | ||
Bivalent DTIs enjoy limited use in circumstances where [[heparin]] would be indicated but cannot be used, such as the [[acute coronary syndrome]] ("unstable angina"). As they are administered by injection ([[intravenous]], [[intramuscular]] or [[subcutaneous]]), they are less suitable for long-term treatment.<ref name=DiNisio/> | Bivalent DTIs enjoy limited use in circumstances where [[heparin]] would be indicated but cannot be used, such as the [[acute coronary syndrome]] ("unstable angina"). As they are administered by injection ([[intravenous]], [[intramuscular]] or [[subcutaneous]]), they are less suitable for long-term treatment.<ref name="DiNisio" /> | ||
Argatroban (as well as the hirudins) are used for [[heparin-induced thrombocytopenia]], a rare but serious complication of heparin treatment that requires anticoagulation (as it increases both arterial and venous [[thrombosis]] risk) but not with the putative agent, heparin.<ref name=DiNisio/> | Argatroban (as well as the hirudins) are used for [[heparin-induced thrombocytopenia]], a rare but serious complication of heparin treatment that requires anticoagulation (as it increases both arterial and venous [[thrombosis]] risk) but not with the putative agent, heparin.<ref name="DiNisio" /> | ||
[[Ximelagatran]] showed good efficacy compared with warfarin in several trials in prevention and treatment of [[deep vein thrombosis]] and as thromboprophylaxis in [[atrial fibrillation]].<ref name=DiNisio/> Development was stopped by manufacturer [[AstraZeneca]], however, because of reports of [[liver enzyme]] derangements and [[liver failure]].<ref>{{cite press release |publisher=AstraZeneca |date=February 14, 2006 |url=http://www.astrazeneca.com/pressrelease/5217.aspx |title=AstraZeneca Decides to Withdraw Exanta }}</ref> Dabigatran is under development for similar indications. | [[Ximelagatran]] showed good efficacy compared with warfarin in several trials in prevention and treatment of [[deep vein thrombosis]] and as thromboprophylaxis in [[atrial fibrillation]].<ref name="DiNisio" /> Development was stopped by manufacturer [[AstraZeneca]], however, because of reports of [[liver enzyme]] derangements and [[liver failure]].<ref>{{cite press release |publisher=AstraZeneca |date=February 14, 2006 |url=http://www.astrazeneca.com/pressrelease/5217.aspx |title=AstraZeneca Decides to Withdraw Exanta }}</ref> Dabigatran is under development for similar indications. | ||
==Monitoring== | ==Monitoring== | ||
There is no [[therapeutic drug monitoring]] widely available for DTIs, in contrast with warfarin (INR) and heparin (APTT). The [[ecarin clotting time]], although not in general clinical use, would be the most appropriate monitoring test.<ref name=DiNisio/> | There is no [[therapeutic drug monitoring]] widely available for DTIs, in contrast with warfarin (INR) and heparin (APTT). The [[ecarin clotting time]], although not in general clinical use, would be the most appropriate monitoring test.<ref name="DiNisio" /> | ||
==Reversal== | |||
[[Idarucizumab]] (Praxbind) can reverse the effects of [[dabigatran]].<ref name="pmid26095746">{{cite journal| author=Pollack CV, Reilly PA, Eikelboom J, Glund S, Verhamme P, Bernstein RA et al.| title=Idarucizumab for Dabigatran Reversal. | journal=N Engl J Med | year= 2015 | volume= 373 | issue= 6 | pages= 511-20 | pmid=26095746 | doi=10.1056/NEJMoa1502000 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26095746 }} </ref> | |||
==Reference== | ==Reference== | ||
<references/> | <references /> | ||
{{Antithrombotics}} | {{Antithrombotics}} | ||
Latest revision as of 15:37, 30 December 2015
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Synonyms and keywords: DTI
Overview
Direct thrombin inhibitors (DTIs) are a class of medication that act as anticoagulants (delaying blood clotting) by directly inhibiting the enzyme thrombin. Some are in clinical use, while others are undergoing clinical development. Several members of the class are expected to replace heparin (and derivatives) and warfarin in various clinical scenarios.
Types
There are two types of DTIs, dependent on their interaction with the thrombin molecule. Bivalent DTIs (hirudin and analogs) bind both to the active site and exosite 1, while univalent DTIs bind only to the active site.[1]
Bivalent
Hirudin and derivatives were originally discovered in Hirudo medicinalis:
- Bivalirudin (transient inhibition - is cleaved by thrombin)
- Desirudin
- Hirudin
- Lepirudin
Univalent
Univalent DTIs include:
- Argatroban
- Dabigatran
- Melagatran (and its prodrug ximelagatran)
Uses
Bivalent DTIs enjoy limited use in circumstances where heparin would be indicated but cannot be used, such as the acute coronary syndrome ("unstable angina"). As they are administered by injection (intravenous, intramuscular or subcutaneous), they are less suitable for long-term treatment.[1]
Argatroban (as well as the hirudins) are used for heparin-induced thrombocytopenia, a rare but serious complication of heparin treatment that requires anticoagulation (as it increases both arterial and venous thrombosis risk) but not with the putative agent, heparin.[1]
Ximelagatran showed good efficacy compared with warfarin in several trials in prevention and treatment of deep vein thrombosis and as thromboprophylaxis in atrial fibrillation.[1] Development was stopped by manufacturer AstraZeneca, however, because of reports of liver enzyme derangements and liver failure.[2] Dabigatran is under development for similar indications.
Monitoring
There is no therapeutic drug monitoring widely available for DTIs, in contrast with warfarin (INR) and heparin (APTT). The ecarin clotting time, although not in general clinical use, would be the most appropriate monitoring test.[1]
Reversal
Idarucizumab (Praxbind) can reverse the effects of dabigatran.[3]
Reference
- ↑ 1.0 1.1 1.2 1.3 1.4 Di Nisio M, Middeldorp S, Büller H (2005). "Direct thrombin inhibitors". N Engl J Med. 353 (10): 1028–40. PMID 16148288.
- ↑ "AstraZeneca Decides to Withdraw Exanta" (Press release). AstraZeneca. February 14, 2006.
- ↑ Pollack CV, Reilly PA, Eikelboom J, Glund S, Verhamme P, Bernstein RA; et al. (2015). "Idarucizumab for Dabigatran Reversal". N Engl J Med. 373 (6): 511–20. doi:10.1056/NEJMoa1502000. PMID 26095746.